The present invention relates generally to solutions which are used in treating the heart. More particularly, the present invention relates to an improved amino acid enriched cardioplegic solution which is designed for use as a solution to be infused directly into the heart in order to either protect the heart against ischemic damage when its blood supply is interrupted (i.e., during routine open heart surgery) or to avoid or reverse ischemic damage to the heart which has been deprived of its blood supply (i.e., acute coronary occlusion) while such blood supply is re-established under controlled conditions (i.e., in the operating room or in the cardiac catheterization laboratory).
This invention was made with Government support under Grant No. HL 16292 awarded by the National Institutes of Health. The Government has certain rights in this invention. The publications and other reference materials referred to herein to describe the background of the invention and to provide additional detail regarding its practice are hereby incorporated by reference. For convenience, the reference materials are numerically referenced and grouped in the Bibliography at the end of the Detailed Description of the Invention.
Cardioplegic solutions are chemical solutions designed to stop the heart and reduce its energy demands during cardiac surgery. They are used by most surgeons worldwide to protect the heart from damage when its blood supply must be interrupted while the cardiac condition is corrected surgically (1,2).
Several years ago, the concept of using oxygenated blood as the vehicle to deliver the cardioplegic solution was introduced (3). This "blood cardioplegia" is usually prepared by first formulating an aqueous solution of concentrated ingredients. The concentrated solution is then diluted with blood and introduced into the heart. This concept of blood cardioplegia was developed from studies of "reperfusion damage" whereby the heart which is deprived of blood supply can be shown to be intact structurally while its blood supply is interrupted, but undergoes dramatic deleterious changes when blood supply is re-established with normal unmodified blood.
Experimental studies have shown that recovery of muscle function can be delayed for up to a month when revascularization occurs after two hours (4) and further, that six hours of coronary flow interruption provides irreversible damage (5). Clinical studies have confirmed that reperfusion with normal blood either in the catheterization laboratory or in the operating room fails to provide immediate recovery of muscle function during hospitalization. Follow-up studies after one year show that revascularization after 6 hours does not restore contractility (6).
Early studies have shown that delivering an initial reperfusate of warm blood with low calcium, alkalosis, and high potassium avoids the above-described damage (7). Subsequent studies have demonstrated that enrichment of the cardioplegic solution with the amino acid glutamate (8,9) and more recently aspartate (10) improve markedly the recovery obtained after cardiac operations in hearts which must undergo operation after they have been damaged acutely.
The amino acid enriched cardioplegic solutions presently in use are made by diluting a previously prepared concentrated aqueous solution with blood or some other diluent containing a source of oxygen to form a cardioplegic solution for intraoperative utilization which includes: an ionic calcium concentration of above 500 umol; a concentration of glucose or other metabolizable substrate of below 400 mg %; a pH of 7.7-7.8; and an osmolarity of below 400 mOsmol.
Although the above described amino acid enriched cardioplegic solutions have markedly improved cardiac recovery, there is still a continuing need to provide even more effective cardioplegic solutions. In addition, it would be desireable to provide cardioplegic solutions which not only prevent heart muscle damage due to ischemia, but also are effective in reversing such damage